The term "intractable vasculitis" is a specific classification term in Japan and it stands for a group of vasculitis syndrome belonging to intractable diseases. According to the "Gist of Measures for Intractable Diseases" issued by the Japanese Government, an intractable disease is defined as: 1) a disease where the cause is ambiguous, the therapeutic method therefor has not been established and there is great risk of sequela, and 2) a disease where the progress is rather chronic and, since it involves both an economic burden and significant labor for nursing etc., home-care is burdensome and mental health is strained. Specific examples of intractable vasculitis, which is one of the syndromes of intractable diseases, defined as such are: periarteritis nodosa (PN), Wegener's granulomatosis (WG), malignant rheumatoid arthritis (MRA), Kawasaki disease vasculitis, Takayasu's arteritis, Buerger's disease, blood vessel Behcet disease, vasculitis of collagen disease, allergic granulomatous vasculitis, nonspecific inflammatory abdominal aortic aneurysm (IAAA), vasculitis related to anti-neutrophil cell antibody (ACNA), anti-phospholipid antibody syndrome and hypersensitive vasculitis. The concept and classification of those intractable diseases are mentioned in detail in a review by Professor Nagasawa (Rinsho Kagaku, 33(11), 1383-1387), etc.
Malignant rheumatoid arthritis (MRA), which is one of the intractable vasculitis diseases, is defined as a disease accompanied by intractable or severe clinical symptoms showing extra-articular symptoms such as vasculitis in addition to the symptoms of chronic rheumatoid arthritis (RA). It had been known that there is a case where RA is accompanied by vasculitis. Then, in 1954, Bevans et al reported two RA cases complicated with nodular polyarteritis-like vasculitis resulting in quick death and they proposed to call such a case "MRA" in view of its bad prognosis. This is the reason for the naming of MRA. In RA, various immune abnormalities such as the presence of rheumatoid factors (RF) in blood are present. However, in MRA, much more and significant abnormalities than common RA are noted, such as an increase of immune complex in blood, lowering of serum complement, and a positive anti-nuclear antibody. Unlike RA where no death occurs, MRA has a characteristic feature that there are many fatal cases due to extra-articular symptoms such as infectious diseases, vasculitis, rheumatoid lung and amyloidosis.
The number of patients suffering from MRA in Japan is estimated to be from 2,000 to 3,000 (about 0.6% of the patients suffering from RA). The age of onset of MRA has a peak in the fifties and that is a bit higher age than in the case of RA. With regard to sexuality, the proportion of male patients is more than the case of RA, and the ratio of patients in terms of male:female is about 1:2. Although MRA shares features with RA, it is characteristic that its extra-articular symptom is more significant than common RA, that the percentage of death thereby is high and that there is an immune abnormality in its base. Accordingly, in the therapy of MRA, it is necessary to take the therapy for an extra-articular symptom into consideration in addition to the therapy for common RA and it is particularly necessary to place more importance on the therapy for immune abnormality.
As an anti-inflammatory therapy, nonsteroidal anti-inflammatory drugs (NSAIDs) and steroidal anti-inflammatory drugs are used for the therapy of RA. Although NSAIDs are the basic therapeutic agents for articular diseases, their efficacy to extra-articular diseases is not so clear. In addition, MRA has a tendency that articular symptoms are ameliorated during the period where the extra-articular symptoms are significant. Thus, it is difficult to evaluate the usefulness of the NSAIDs in the therapy of MRA and that has not been clarified yet. On the other hand, steroids are used as basic therapeutic agents for RA. However, since the onset of MRA often happens due to a sudden increase or decrease of steroids, it has been said that their use must be careful. It has been reported that a steroid pulse therapy where intravenous drip infusion of 1,000 mg of methylpredonisolone is carried out for three days is useful for severe refractory RA and is useful not only for improvement in clinical symptoms but also for suppression of immune complex in blood and RF. However, when the pulse therapy is finished, there is a tendency that the state returns to the previous one within a relatively short period. Therefore, to maintain the effect, it is necessary to also conduct immunotherapy together with the pulse therapy. Although it is likely that the pulse therapy is effective for MRA symptoms, the effect is not long-lasting and the said therapy is not able to be repeated frequently. Accordingly, pulse therapy is considered to be an emergency therapy at present.
With regard to the drugs for immunotherapy, immunomodulators and immunosuppressants are used. Slowly-acting anti-rheumatic agents such as gold sodium thiomalate (GST) and d-penicillamine (d-p) are classified as immunomodulators because of a sense that they improve the immune abnormality of RA but do not suppress the normal immune mechanism. It is believed that GST mainly functions via the macrophage mechanism while d-p improves RA by means of suppression of T-helper cell function. However, immunomodulators are slow-acting and do not serve the purpose when used after an MRA symptom occurs. In addition, their efficacy towards severe MRA symptoms has not been confirmed yet.
Although steroids and NSAIDs have an immunosuppressing action, the term "immunosuppressant" usually means cytotoxic drugs such as cyclophosphamide (CY), azathioprine (AZ), methotrexate (MTX), etc. and cyclosporin A (CsA). CY is an alkylating agent and damages DNA by inhibiting its synthesis whereby it achieves an immunosuppressing action. Although this agent has been proved to be effective towards RA by a double blind test, its allowed use is limited to severe RA where common therapy is not effective due to its strong side effect. It has also been reported that they are effective towards vasculitis. AZ and MTX are antimetabolic immunosuppressants and it has been reported that, although they have weaker side effects than CY, their immunosuppressing action is weak as well. Effect of the MTX therapy to MRA is ambiguous and it is believed that its intermittent administration in low doses will probably have a therapeutic significance only as an immunomodulator. The action mechanism of CsA is believed to be mostly due to suppression against IL-2 production of the T-helper cell function and due to inhibition against IL-2 receptor expression of cytotoxic cells. With regard to the efficacy of CsA towards RA, Dougados et al reported that, in a double blind test, it showed a significant improving effect compared to the control group but it resulted in nephropathy in about one half of the treated group.
As mentioned above, the drugs used for the therapy of intractable vasculitis such as malignant rheumatoid arthritis at present have their merits and demerits in view of expression of pharmaceutical effects and onset of side effects. Thus, no suitable therapeutic agent has yet been found and there is a strong demand in the clinical field for therapeutic agents having high safety and strong therapeutic effect.
Several compounds of the present invention were found as novel substances having growth suppressing action to plants. As a result of subsequent investigations, those compounds including analogs thereof have been found to have pharmacological actions such as hypoglycemic action and hypolipemic action and to exhibit low toxicity resulting in almost no side effects. See U.S. Pat. Nos. 4,647,574 and 4,683,240, each to lenaga et al and Japanese Laid-Open Patent Publications Sho-57/114578, Sho-60/188373, Sho-61/122275, Sho-62/45525, Sho-62/14, Hei-01/75473, Hei-01/299276, etc.). It has been also reported that the compounds of the present invention are useful as agents for lowering uremic toxin (Japanese Laid-Open Patent Publication Hei-03/72463) and further that they are useful as eliminators of active oxygen and free radicals (Japanese Laid-Open Patent Publication Hei-09/227377). However, none of the above-mentioned patent publications, describe a therapeutic effect of the compounds of the present invention for intractable diseases such as malignant rheumatoid arthritis and, in addition, there has been no report suggesting that at all.
The present inventors have carried out intensive investigations and have found that the hydantoin derivatives of the present invention have a therapeutic effect for malignant rheumatoid arthritis whereupon the present invention has been accomplished. The compounds of the present invention are less toxic and have almost no side effect, and accordingly they are quite useful as safe drugs for the therapy of intractable vasculitis such as malignant rheumatoid arthritis.
The present invention solves the above-mentioned problems and provides a highly safe therapeutic agent for intractable diseases such as malignant rheumatoid arthritis which has been strongly demanded by patients and the clinical field.